Synthesis of novel 3,5-dichloro-2-arylpyridines by palladium acetate-catalyzed ligand-free suzuki reactions in aqueous media

Article abstract of DOI:10.3390/molecules14093153

A highly efficient palladium acetate-catalyzed ligand-free Suzuki reaction of 2,3,5-trichloropyridine with arylboronic acids in aqueous phase was developed. High yields of 3,5-dichloro-2-arylpyridines, a simple Pd source, absence of ligands, and environme

Full text of DOI:10.3390/molecules14093153

Molecules 2009, 14, 3153-3160; doi:10.3390/molecules14093153
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Novel 3,5-Dichloro-2-arylpyridines by Palladium
Acetate-Catalyzed Ligand-Free Suzuki Reactions in Aqueous
Media
Huanan Hu 1,*, Changhua Ge 1, Anjiang Zhang 2 and Lisheng Ding 3
1
College of Pharmaceutial and Chemical Engineering, Taizhou University, Linhai 317000, China
2
Ningbo Institute of Material Technology and Engineering, Chinese Academy of Sciences, Ningbo
315201, China
3
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
* Author to whom correspondence should be addressed; E-mail: hhn12192000@yahoo.com.cn;
Tel.: +86-576 85578089; Fax: +86-576 85137004.
Received: 19 July 2009; in revised form: 18 August 2009 / Accepted: 25 August 2009 /
Published: 26 August 2009
Abstract: A highly efficient palladium acetate-catalyzed ligand-free Suzuki reaction of
2,3,5-trichloropyridine with arylboronic acids in aqueous phase was developed. High
yields of 3,5-dichloro-2-arylpyridines, a simple Pd source, absence of ligands, and
environmentally benign as well as mild reaction conditions are important features of this
method.
Keywords: Suzuki reaction; ligand-free; aqueous phase; 2,3,5-trichloropyridine; 3,5-
dichloro-2-arylpyridines
Introduction
Heterocyclic compounds used as medicines and pesticides have developed rapidly in recent years
and have become the new trend [1]. Both natural and artificial heterocyclic compounds are all very
important in medicine and pesticide research. There are numerous examples in the literature of the
biological activity of biaryls with pyridine rings, which are used in pharmaceuticals [2-5], herbicides
[6-8] and even light emitting materials [9-14]. Palladium-catalyzed cross-coupling of aryl halides with
organoboronic acids, known as the Suzuki cross-coupling reaction, is a versatile and highly utilized

Molecules 2009, 14
3154
reaction for the selective formation of carbon–carbon bonds, in particular for the synthesis of
biaryls [2-5]. Recently, efforts have been focused on the development of efficient and selective
catalytic systems for the Suzuki reaction, but many such catalytic systems are limited to the couplings
of aromatic iodides and bromides because of the much higher energy is required for the oxidative
insertion of palladium catalysts into the C-Cl bond of aryl chlorides [5,14-20]. In recent years, the use
of readily available aryl chlorides in these transformations has received increasing attention, and a
number of effective catalytic systems have been developed for this purpose [18-20]. In these processes,
the use of sterically hindered and electron-rich ligands played crucial roles in the coupling of these
challenging substrates. However, the reaction carried out in conventional organic solvents suffers from
several drawbacks including high catalyst consumption, high reaction temperatures and decomposition
of catalyst, which place significant limits on their synthetic applications.
There have been few reports on palladium catalyzed ligand-free Suzuki coupling of heteroaromatic
chloride with arylboronic acids in aqueous phase. 2,3,5-Trichloropyridine can be used as intermediate
for the production of active herbicidal substances [21,22]. Herein, we presented a palladium acetate-
catalyzed ligand-free Suzuki coupling of 2,3,5-trichloropyridine with arylboronic acids in aqueous
phase, and its use in the regioselective synthesis of a series of novel 3,5-dichloro-2-arylpyridines. Of
interest was the fact that no di- or tri-substituted products were obtained in these reactions.
Scheme 1. Suzuki coupling of 2,3,5-trichloropyridine with arylboronic acids.
Cl
Cl
Cl
Cl
Cl
Pd(OAc)2
0.5 mol%
Ar-B(OH)2
+
Na2CO3
H2O-DMF
N
Ar
N
1
2
3
Results and Discussion
Wallow and co-workers [23] have reported an improved method for ligandless Suzuki couplings
using 1:1 acetone/water as solvent. However, the attractiveness of their protocol is limited by the
painstaking measures used to exclude oxygen, including a total of 15 freeze-pump-thaw degassing
cycles at various stages of the reaction. Liu and co-workers [24] have reported that a highly efficient
palladium acetate-catalyzed ligand-free Suzuki reaction of aryl iodides and bromides with arylboronic
acids in aqueous phase took place with short reaction times (0.5-1 h) at 35 °C in air. The key for such a
successful catalytic system was the use of a suitable amount of an organic cosolvent, with the best
ratio being a 3.5:3 mixture of water and organic solvent. We have used conditions similar to those
described by Liu to study a ligand-free Suzuki coupling of 2,3,5-trichloropyridine with arylboronic
acids in aqueous phase (Scheme 1).
For the investigation of reaction conditions for the ligand-free Suzuki coupling of 2,3,5-
trichloropyridine with arylboronic acids in aqueous phase, we chose the reaction of 2,3,5-
trichloropyridine with phenylboronic acid as a model. We initially studied the effect of a solvent on the
yields. The reactions were carried out using Na2CO3 as base in a 3.5:3 mixture of water and organic
solvent in the presence of 0.5 mol % Pd(OAc)2 in air. We found the use of ethanol, propanol, acetone

Molecules 2009, 14
3155
and DMF as cosolvents all gave good yields (Table 1, entries 1-4), and DMF was found to be the best
solvent, whereas toluene, CH2Cl2 and THF provided very low yields (Table 1, entries 5-7). We found
that the best yield of 3a was obtained when the reaction temperature was increased to 60 °C in
DMF/H2O (3:3.5 mL) (Table 1, entries 4, entries 8). However, reaction yields decreased as the
reaction temperature was increased. The results are shown in Table 1.
Table 1 Effect of solvent on the Suzuki reaction a.
Entry
Solvent (3:3.5 mL)
acetone/H2O
ethanol/H2O
propanol/H2O
DMF/H2O
Yieldb (%)
1
2
3
4
5
81
80
79
83
29
34
21
89
DCM/H2O
THF/H2O
Toluene/H2O
DMF/H2O
6
7
8c
a Reaction conditions: 2,3,5-trichloropyridine (1 mmol), phenylboronic acid (1.5 mmol), Na2CO3
b
(2 mmol), Pd(OAc)2 (0.5% mmol), H2O/solvent =3.5:3 mL, at 35 °C, for 12 h; Isolated yields;
c Reaction time at 60 °C
We also surveyed the effect of reaction time on the yields using DMF as cosolvent. The best yields
could be obtained after 12 h at 60 °C, and the reaction yields decreased for more than or less than 12 h.
The results are given in Table 2.
Table 2 Effect of reaction time on the Suzuki reaction a.
Time/h
4
55
6
61
8
79
10
85
12
89
14
87
Yieldb/%
a Reaction conditions: 2,3,5-trichloropyridine (1 mmol), phenylboronic acid (1.5 mmol), Na2CO3 (2
mmol), Pd(OAc)2 (0.5 % mmol), H2O/DMF =3.5:3 mL, at 60°C; b Isolated yields.
Under the optimized reaction conditions [Pd(OAc)2 as catalyst, Na2CO3 as base and H2O/DMF as
cosolvent], a series of novel 3,5-dichloro-2-arylpyridines were regioselectively synthesized by
palladium acetate-catalyzed ligand-free Suzuki reaction in aqueous phase, and results are summarized
in Table 3.
Aryl boronic acids with electron withdrawing substituted groups, which are less nucleophilic and,
hence, transmetalate more slowly than electron-neutral analogues, are prone to homocoupling and
protodeboronation side reactions [25]. However, in our system, both the electron rich and the electron-
deficient arylboronic acids afforded the corresponding products in good yields.
Because much higher energy is required for the oxidative insertion of palladium catalysts into the
C-Cl bond of aryl chlorides, transformations of these substrates remain a significant challenge in
organic synthesis. We have regioselectively synthesized a series of 3,5-dichloro-2-arylpyridines, and
no di- or tri-substituted products were found in these reactions, so the reaction of different substituted
chloropyridines with arylboronic acid were studied, and the results were summarized in Table 4.

Molecules 2009, 14
Table 3 Suzuki coupling of 2,3,5-trichloropyridine with arylboronic acids a.
3156
Entry
Arylboronic acid
Product(3)
3a
Yieldb (%)
1
89
B(OH)
2
Me
B(OH)
2
2
3
3b
3c
90
87
B(OH)2
B(OH)
Me
Cl
F
2
4
5
6
7
3d
3e
3f
91
89
85
88
B(OH)2
B(OH)2
B(OH)2
H3CO
3g
F3C
B(OH)2
8
3h
82
O2N
S
B(OH)2
B(OH)
9
3i
3j
86
89
2
10
a Reaction conditions: 2,3,5-trichloropyridine (1 mmol), arylboronic acid (1.5 mmol), Na2CO3 (2
mmol), Pd(OAc)2 (0.5 % mmol), H2O/DMF = 3.5:3 mL, at 60°C, for 12 h; b Isolated yields
Table 4. Suzuki coupling of different chloropyridines with phenylboronic acids a.
Entry
chloropyridine
phenylboronic acid
Product
Yieldb(%)
1
76
trace
89
B(OH)
2
Cl
N
N
4
2
3
B(OH)
B(OH)
2
2
Cl
N
N
5
Cl
3a
Cl
Cl
N
a Reaction conditions: chloropyridine (1 mmol), phenylboronic acid (1.5 mmol), Na2CO3 (2 mmol),
H2O/DMF = 3.5:3 mL, at 60 °C, for 12 h; b Isolated yields.
We found 2-chloropyridine, which is electron deficient, afforded the products in 76% yield, while
3-chloropyridine was almost inactive. We also found 2,3,5-trichloropyridine gave better yields as
compared to 2-chloropyridine, we conjectured the activity of 2-position chlorine in 2,3,5-
trichloropyridine was enhanced because of the withdrawing action on ortho nitrogen and 3,5-position
chlorine, hence, 3,5-dichloro-2-arylpyridines were regioselectively synthesized in mild reaction
conditions.

Molecules 2009, 14
3157
Conclusions
In conclusion, a highly efficient and environmentally friendly protocol to synthesis of novel 3,5-
dichloro-2-arylpyridines has been developed. Important features of present method include a simple Pd
source, no need for ligands, environmentally benign and mild reaction conditions and good yields.
Further studies on the biological activity of 3,5-dichloro-2-arylpyridines are in progress.
Experimental
General
All melting points were determined on an XT-4A apparatus and are uncorrected. TLC was
performed using precoated silica gel GF254 (0.25 mm), column chromatography was performed using
silica gel (200-300 mesh). The 1H- and 13C-NMR spectra were measured at 25 °C at 300 and 75 MHz,
respectively, on a Bruker Advance 300 spectrometer, using TMS as internal standard. J-values are
given in Hz. The IR spectra were taken on a Bruker Vector 55 spectrometer. Elemental analyses were
carried out with an EA 1112 elemental analyzer. 2,3,5-Trichloropyridine (1) was prepared according
to the reported procedure [21]. Aryl bromides were used directly as obtained commercially unless
otherwise noted.
Typical procedure for the preparation of 3,5-dichloro-2-arylpyridines 3
A mixture of Na2CO3 (0.212 g, 2 mmol), Pd(OAc)2 (1 mg, 0.5 mol %), 2,3,5-trichloropyridine
(1 mmol), arylboronic acid (1.5 mmol), distilled water (3.5 mL) and DMF (3 mL) was stirred at 60 °C
for 12 h. Afterward, the reaction solution was extracted four times with diethyl ether (4 × 10 mL). The
combined organic extract was concentrated under reduced pressure and the residue was subjected to
chromatography on a column of silica gel, eluting with petroleum ether and ethyl acetate. The eluate
was cocentrated under reduced pressure, giving compounds 3a–j.
1
3,5-Dichloro-2-phenylpyridine (3a): Colorless solid; m.p. 38-39 °C; H-NMR (CDCl3) δ: 8.55 (d,
J = 2.1 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.70 (m, 2H), 7.48 (m, 2H), 7.33 (m, 1H); 13C-NMR (CDCl3)
δ: 154.7, 146.5, 137.4, 133.8, 130.4, 130.1, 129.2, 128.5, 128.1; IR (KBr) ν: 3057, 1616, 1565, 1430,
1370, 1199, 1115 cm-1; Anal. Calcd. for C11H7Cl2N: C, 58.96; H, 3.15; N, 6.25. Found: C, 59.12; H,
3.18; N, 6.19%.
1
3,5-Dichloro-2-p-tolylpyridine (3b): Colorless solid; m.p. 51-52 °C; H-NMR (CDCl3) δ: 8.53 (d,
13
J = 2.1 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.30 (m, 1H), 2.41 (s, 3H); C-
NMR (CDCl3) δ: 146.4, 139.1, 137.3, 134.4, 133.8, 130.1, 129.2, 128.8, 128.4, 21.3; IR (KBr) ν: 3053,
2918, 1612, 1565, 1431, 1372, 1195, 1111 cm-1; Anal. Calcd. for C12H9Cl2N: C, 60.53; H, 3.81; N,
5.88. Found: C, 60.45; H, 3.86; N, 5.94%.
3,5-Dichloro-2-o-tolylpyridine (3c): Yellowish oil; 1H-NMR (CDCl3) δ: 8.55 (d, J = 2.1 Hz, 1H), 7.83
(d, J = 2.1 Hz, 1H), 7.28 (m, 4H), 2.15 (s, 3H); 13C-NMR (CDCl3) δ: 156.2, 146.3, 137.1, 136.6, 135.9,
131.4, 130.7, 130.2, 128.9, 128.8, 125.7, 19.4; IR (film) ν: 3055, 2923, 1649, 1533, 1432, 1368, 1196,

Molecules 2009, 14
3158
1114 cm-1; Anal. Calcd. for C12H9Cl2N: C, 60.53; H, 3.81; N, 5.88. Found: C, 60.63; H, 3.86; N,
5.79%.
3,5-Dichloro-2-(4-chlorophenyl)pyridine (3d): Colorless solid; m.p. 126-127 °C; 1H-NMR (CDCl3) δ:
13
8.54 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.38 (m, 2H); C-NMR
(CDCl3) δ: 1543.4, 146.6, 143.4, 137.5, 135.4, 130.7, 130.0, 128.4, 122.7; IR (KBr) ν: 3065, 1595,
1564, 1488, 1435, 1364, 1199, 1115 cm-1; Anal. Calcd. for C11H6Cl3N: C, 51.10; H, 2.34; N, 5.42.
Found: C, 50.97; H, 2.35; N, 5.48%.
1
3,5-Dichloro-2-(4-fluorophenyl)pyridine (3e): Colorless solid; m.p. 119-121 °C; H-NMR (CDCl3) δ:
13
8.53 (d, J = 2.1 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.71 (m, 2H), 7.15 (m, 2H); C-NMR (CDCl3) δ:
164.8, 161.5, 153.6, 146.5, 137.5, 133.1, 131.3(q, J = 8.3 Hz, 1C), 130.5, 115.2(q, J = 21.7 Hz, 1C); IR
(KBr) ν: 3046, 1602, 1565, 1508, 1437, 1367, 1166, 1119 cm-1; Anal. Calcd. for C11H6Cl2FN: C,
54.58; H, 2.50; N, 5.79. Found: C, 54.19; H, 2.53; N, 5.86%.
1
3,5-Dichloro-2-(4-methoxyphenyl)pyridine (3f): Colorless solid; m.p. 86-88 °C; H-NMR (CDCl3) δ:
8.51 (d, J = 2.1 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H),
3.84 (s, 3H); 13C-NMR (CDCl3) δ: 160.3, 154.2, 146.4, 137.4, 130.8, 129.8, 129.7, 129.5, 113.5, 55.3;
IR (film) ν: 3048, 2926, 1606, 1509, 1434, 1366, 1175, 1113 cm-1; Anal. Calcd. for C12H9Cl2NO: C,
56.72; H, 3.57; N, 5.51. Found: C, 56.66; H, 3.60; N, 5.47%.
1
3,5-Dichloro-2-(3-(trifluoromethyl)phenyl)pyridine (3g): Yellowish oil; H-NMR (CDCl3) δ: 8.57 (d,
J = 2.1 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.79-7.85 (m, 2H), 7.56-7.71 (m, 2H); 13C-NMR (CDCl3) δ:
153.0, 146.7, 143.4, 139.0, 137.7, 132.6, 131.2 (q, J = 34.5 Hz, 1C), 128.6, 126.5, 125.8, 123.8 (q,
J = 271.3 Hz, 1C); IR (film) ν: 3067, 2923, 1616, 1565, 1490, 1425, 1373, 1169, 1128 cm-1; Anal.
Calcd. for C12H6Cl2F3N: C, 49.34; H, 2.07; N, 4.80. Found: C, 49.41; H, 2.10; N, 4.71%.
1
3,5-Dichloro-2-(3-nitrophenyl)pyridine (3h): Colorless solid; m.p. 107-108 °C; H-NMR (CDCl3) δ:
8.64 (d, J = 1.6 Hz,, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.27-8.31 (m, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.88 (d,
13
J = 1.6 Hz, 1H), 7.55-7.80 (m, 1H); C-NMR (CDCl3) δ: 151.9, 146.9, 146.0, 138.5, 137.7, 135.3,
131.7, 130.2, 129.2, 124.5, 123.4; IR (KBr) ν: 3056, 1617, 1565, 1485, 1431, 1348, 1118 cm-1; Anal.
Calcd. for C11H6Cl2N2O2: C, 49.10; H, 2.25; N, 10.41. Found: C, 49.23; H, 2.25; N, 10.39%.
3,5-Dichloro-2-(thiophen-3-yl)pyridine (3i): Colorless solid; m.p. 42-43 °C; 1H-NMR (CDCl3) δ: 8.49
(d, J = 2.1 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.68-7.78 (m, 1H), 7.30-7.38 (m, 2H); 13C-NMR (CDCl3)
δ: 149.4, 146.3, 137.6, 133.7, 129.6, 128.6, 128.1, 127.2, 125.0; IR (KBr) ν: 3048, 1615, 1562, 1432,
1373, 1195, 1111 cm-1; Anal. Calcd. for C9H5Cl2NS: C, 46.98; H, 2.19; N, 6.09. Found: C, 47.06; H,
2.17; N, 6.14%.
1
3,5-Dichloro-2-(naphthalen-1-yl)pyridine (3j): Colorless solid; m.p. 63-64 °C; H-NMR (CDCl3) δ:
13
8.65 (d, J = 2.0 Hz, 1H), 7.91-7.99 (m, 3H), 7.70 (m, 2H), 7.44-7.57 (m, 5H); C-NMR (CDCl3) δ:
155.2, 146.5, 136.9, 134.9, 133.5, 132.2, 131.1, 130.9, 129.4, 128.5, 127.2, 126.5, 126.0, 125.1, 124.9;
IR (KBr) ν: 3056, 1612, 1566, 1454, 1380, 1189, 1115 cm-1; Anal. Calcd. for C15H9Cl2N: C, 65.72; H,
3.31; N, 5.11. Found: C, 65.81; H, 3.35; N, 5.01%.

Molecules 2009, 14
3159
Typical Procedure for the preparation of 2-phenylpyridine (4)
A mixture of Na2CO3 (0.212 g, 2 mmol), Pd(OAc)2 (1 mg, 0.5 mol %), 2-chloropyridine (1 mmol),
phenylboronic acid (1.5 mmol), distilled water (3.5 mL) and DMF (3 mL) was stirred at 60 °C for
12 h. Afterward, the reaction solution was extracted four times with diethyl ether (4×10 mL). The
organic solvent was removed under reduced pressure. The residue was subjected to chromatography on
a column of silica gel, eluting with petroleum ether and ethyl acetate, and the solvent was removed
1
under reduced pressure, giving compound 4. Yellowish oil; H-NMR (CDCl3) δ: 8.59 (d, J = 4.8 Hz,
1H), 7.99 (d, J = 6.8 Hz, 2H), 7.78–7.71 (m, 2H), 7.48 (t, J = 8.8Hz, 2H), 7.42 (t, J = 7.2Hz, 1H), 7.26–
13
7.21 (m, 1H); C-NMR (CDCl3) δ: 157.4, 149.6, 139.3, 136.7, 128.9, 128.7, 126.9, 122.1, 120.5; IR
(film) ν: 3056, 1610, 1565, 1450, 1316, 1182, 1095 cm-1.
Acknowledgement
We are grateful for financial support from the Nature Science Foundation of Zhejiang Province,
China (Project No. Y407350)
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Sample Availability: Samples of the compounds 3a-j are available from the authors.
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